Biology subjects

Amary, F.

Publications and source records attributed to Amary, F..

4 recordsLinked to original sources

bioRxiv2024

SAVANA: reliable analysis of somatic structural variants and copy number aberrations in clinical samples using long-read sequencing

Accurate detection of somatic structural variants (SVs) and copy number aberrations (SCNAs) is critical to inform the diagnosis and treatment of human cancers. Here, we describe SAVANA, a computationally efficient algorithm designed for the joint analysis of somatic SVs, SCNAs, tumour purity and ploidy using long-read sequencing data. SAVANA relies on machine learning to distinguish true somatic SVs from artefacts and provide prediction errors for individual SVs. Using high-depth Illumina and nanopore whole-genome sequencing data for 99 human tumours and matched normal samples, we establish best practices for benchmarking SV detection algorithms across the entire genome in an unbiased and data-driven manner using simulated and sequencing replicates of tumour and matched normal samples. SAVANA shows significantly higher sensitivity, and 9- and 59-times higher specificity than the second and third-best performing algorithms, yielding orders of magnitude fewer false positives in comparison to existing long-read sequencing tools across various clonality levels, genomic regions, SV types and SV sizes. In addition, SAVANA harnesses long-range phasing information to detect somatic SVs and SCNAs at single-haplotype resolution. SVs reported by SAVANA are highly consistent with those detected using short-read sequencing, including complex events causing oncogene amplification and tumour suppressor gene inactivation. In summary, SAVANA enables the application of long-read sequencing to detect SVs and SCNAs reliably in clinical samples.

cancer biology↗

bioRxiv2023

Mechanisms underpinning osteosarcoma genome complexity and evolution

Osteosarcoma is the most common primary cancer of bone with a peak incidence in children and young adults. Despite progress, the genomic aberrations underpinning osteosarcoma evolution remain poorly understood. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of tumours. Chromothripsis drives the acquisition of oncogenic mutations and generates highly unstable derivative chromosomes, the evolution of which drives clonal diversification and intra-tumour heterogeneity. In addition, we report a novel mechanism, loss-translocation-amplification (LTA) chromothripsis, which mediates rapid malignant transformation and punctuated evolution in about half of paediatric and adult high-grade osteosarcomas. Specifically, a single double-strand break triggers concomitant TP53 inactivation and segmental amplifications, often amplifying oncogenes to high copy numbers in extrachromosomal circular DNA elements through breakage-fusion-bridge cycles involving multiple chromosomes. LTA chromothripsis is detected at low frequency in soft-tissue sarcomas, but not in epithelial cancers, including those driven by TP53 mutation. Finally, we identify genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.

cancer biology↗

bioRxiv2021

Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone.

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGF{beta}-like soluble factor, SCUBE3. In turn, osteoclasts secrete unregulated amounts of SEMA4D enhancing proliferation of mutated osteoprogenitors and arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation upon denosumab treatment, a drug that depletes osteoclasts. In contrast, gain of hTERT activity, commonly found in malignant GCT, makes neoplastic cells insensitive to osteoclasts, predicting the unresponsiveness to denosumab. We provide a mechanism for GCT initiation and its response to current treatment, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells, emphasising the importance of tumor/microenvironment bidirectional interactions in tumorigenesis.

cancer biology↗

bioRxiv2018

Epigenetic inactivation of oncogenic brachyury (TBXT) by H3K27 histone demethylase controls chordoma cell survival

The expression of the transcription factor brachyury (TBXT) is normally restricted to embryonic development and its silencing after mesoderm development is epigenetically regulated. In chordoma, a rare tumour of notochordal differentiation, TBXT acts as a putative oncogene, and we hypothesised that its expression could be controlled through epigenetic inhibition. Screening of five chordoma cell lines revealed that only inhibitors of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (Jmjd3) reduce TBXT expression and lead to cell death, findings validated in primary patient-derived culture systems. Pharmacological inhibition of KDM6 demethylases leads to genome-wide increases in repressive H3K27me3 marks, accompanied by significantly reduced TBXT expression, an effect that is phenocopied by the dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Transcriptional profiles in response to a novel KDM6A/B inhibitor, KDOBA67, revealed downregulation of critical genes and transcription factor networks for chordoma survival pathways, whereas upregulated pathways were dominated by stress, cell cycle and pro-apoptotic response pathways.\n\nThis study supports previous data showing that the function of TBXT is essential for maintaining notochord cell fate and function and provides further evidence that TBXT is an oncogenic driver in chordoma. Moreover, the data suggest that TBXT can potentially be targeted therapeutically by modulating epigenetic control mechanisms such as H3K27 demethylases.

cancer biology↗